Rheumatoid arthritis (RA) is a chronic inflammatory disease of unknown etiology. It is characterized by synovial inflammation with frequent progression to articular cartilage and bone destruction. The syovial inflammatory response in RA consists predominately of T lymphocytes, mostly T helper cells (Th), with fewer numbers of macrophages and B lymphocytes. The Th cells can be divided into two overlapping subpopulations of important functional significance, Th1 and Th2 cells. Th1 cells secrete IL-2 and interferon- and regulate cell-mediated responses. Th2 cells secrete IL-4, IL-5, and IL-10, and mediate humoral responses. Most of Th cells in the rheumatoid joint appear to belong to the Th1 subpopulation. The synovial tissue in RA exhibits other features typical of a cell-mediated response, including hypervascularity, upregulation of cell adhesion molecules, and overexpression of pro-inflammatory cytokines such as IL-1 and tumor necrosis factor (TNF)- . IL-10, a cytokine produced by Th2 cells and macrophages, has primarily immunosuppressive and anti-inflammatory properties. The inhibitory effects of IL-10 have been observed in animal models of arthritis where it can ameliorate joint inflammation. The purpose of the present study was to determine the safety and tolerability and potential clinical efficacy of subcutaneous doses of recombinant human IL-10 (rHuIL-10) in patients with RA. The study was a multicenter, double-blind, placebo- controlled, escalating dose (0.5, 1, 5, 10, and 20 5g/d) clinical trial with a dosing period of 28 days. The main outcomes for the study were the frequency and severity of adverse effects and the American College of Rheumatology Core Disease Measures. The study has been completed. Our site enrolled 8 patients (3 males and 5 females) in the study of a total of 69 patients. The results showed that the study drug was well-tolerated and did not cause any serious adverse reactions. Platelet counts dropped significantly in several patients receiving the two highest doses of IL-10, with platelet counts in 2 cases dropping below 100,000/mm3. There were no bleeding complications, and the thrombocytopenia was quickly reversible. No responders were noted in the two lowest dosage cohorts, but in the 5 5g/d dosage cohort, 3 of 8 patients were classified as responders. These preliminary results suggest that IL-10 therapy may offer some clinical benefits to patients with RA without causing major toxicity. Significance: RA is widely believed to be a Th1-mediated disease, although the data to support this hypothesis is circumstantial. For example, Th1 cells are associated with cellular immune responses, which seems to fit with the characteristics of rheumatoid joint inflammation, and T cell clones isolated from synovial tissue of RA patients most often secrete Th1 cytokines. Additional insights into whether RA is a Th-driven response in RA may be obtained by examining the treatment and biological effects of cytokines which downregulate Th1 responses.